This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tetracyclines moderate inflammatory responses of various etiologies. We hypothesized that tetracyclines exerted, in addition to antimicrobial function, control over inflammation elicited by Borrelia burgdorferi. To model systemic effects we used the human monocytic cell line THP-1, and for effects in the central nervous system we employed rhesus monkey brain astrocytes and microglia. Cells were stimulated with live or sonicated B. burgdorferi, or the OspA lipoprotein, in the presence of increasing concentrations of doxycycline or minocycline. Both antibiotics significantly reduced the production of TNF-alpha, IL-6, and IL-8 in a dose-dependent manner in all cell types. Microarray analyses of the effect of doxycycline on gene transcription in spirochete-stimulated monocytes revealed that the NF[unreadable]B and IKK-alpha genes were down-regulated. Functionally, phosphorylation of I[unreadable]B-alpha and binding of NF[unreadable]B to target DNA were both reduced in these cells. Our results prove the principle that tetracyclines may have a dual therapeutic effect in Lyme disease.